glycoursodeoxycholic-acid and Obesity

Bile acid profiles are altered in obese individuals with asthma. Thus, we sought to better understand how obesity-related systemic changes contribute to lung pathophysiology. We also test the therapeutic potential of nitro-oleic acid (NO

Topics: Adolescent; Adult; Animals; Anti-Asthmatic Agents; Antigens, Dermatophagoides; Asthma; Bile Acids and Salts; Diet, High-Fat; Drug Evaluation, Preclinical; Fatty Acids; Female; Forced Expiratory Volume; Glycocholic Acid; Humans; Liver; Lung; Male; Mice; Mice, Inbred C57BL; Middle Aged; Nitro Compounds; Obesity; Oleic Acids; Respiratory Hypersensitivity; Thinness; Ursodeoxycholic Acid; Vital Capacity; Young Adult

Recent studies reveal that bile acid metabolite composition and its metabolism are changed in metabolic disorders, such as obesity, type 2 diabetes and metabolic associated fatty liver disease (MAFLD), yet its role and the mechanism remain largely unknown. In the present study, metabolomic analysis of 163 serum and stool samples of our metabolic disease cohort was performed, and we identified glycoursodeoxycholic acid (GUDCA), glycine-conjugated bile acid produced from intestinal bacteria, was decreased in both serum and stool samples from patients with hyperglycemia. RNA-sequencing and quantitative PCR results indicated that GUDCA alleviated endoplasmic reticulum (ER) stress in livers of high fat diet (HFD)-fed mice without alteration of liver metabolism. In vitro, GUDCA reduced palmitic acid induced-ER stress and -apoptosis, as well as stabilized calcium homeostasis. In vivo, GUDCA exerted effects on amelioration of HFD-induced insulin resistance and hepatic steatosis. In parallel, ER stress and apoptosis were decreased in GUDCA-treated mice as compared with vehicle-treated mice in liver. These findings demonstrate that reduced GUDCA is an indicator of hyperglycemia. Supplementation of GUDCA could be an option for the treatment of diet-induced metabolic disorders, including insulin resistance and hepatic steatosis, with inhibiting ER stress.

Topics: Animals; Diet, High-Fat; Endoplasmic Reticulum Stress; Fatty Liver; Female; Humans; Lipid Metabolism; Liver; Male; Metabolic Diseases; Middle Aged; Obesity; Ursodeoxycholic Acid

The anti-hyperglycemic effect of metformin is believed to be caused by its direct action on signaling processes in hepatocytes, leading to lower hepatic gluconeogenesis. Recently, metformin was reported to alter the gut microbiota community in humans, suggesting that the hyperglycemia-lowering action of the drug could be the result of modulating the population of gut microbiota. However, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of metformin remained elusive. Here, we performed metagenomic and metabolomic analysis of samples from individuals with newly diagnosed type 2 diabetes (T2D) naively treated with metformin for 3 d, which revealed that Bacteroides fragilis was decreased and the bile acid glycoursodeoxycholic acid (GUDCA) was increased in the gut. These changes were accompanied by inhibition of intestinal farnesoid X receptor (FXR) signaling. We further found that high-fat-diet (HFD)-fed mice colonized with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin treatment on glucose intolerance were abrogated. GUDCA was further identified as an intestinal FXR antagonist that improved various metabolic endpoints in mice with established obesity. Thus, we conclude that metformin acts in part through a B. fragilis-GUDCA-intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia.

Topics: Bacteroides; Bile Acids and Salts; Diabetes Mellitus, Type 2; Diet, High-Fat; Gastrointestinal Microbiome; Gene Expression Regulation, Bacterial; Glucose Intolerance; Humans; Hyperglycemia; Metabolome; Metagenomics; Metformin; Obesity; Receptors, Cytoplasmic and Nuclear; Ursodeoxycholic Acid